1. Field of the Invention
This invention relates to a one-step process to prepare triazole carboxylic acids from azides and xcex2-ketoesters.
2. Description of the Related Art
The 1,2,3-triazole unit is an important element in a number of drugs and development candidates. The triazole is a structural backbone of many antibiotics, antiallergics, antimetastasis agents, anticonvulsants and antidepressants. Their synthesis usually involves the reaction of organic azides with unsaturated compounds. Such unsaturated compounds are usually acetylenic compounds (Hiroto et al., Chem Pharm. Bull. 1990, 38(9), 2597-2601; Palacios et al., Heterocycles 1994, 38(1), 95-102), as, for example, acetylene dicarboxylic acid derivatives. Because these acetylenic starting materials usually carry the same substituents on both acetylenic carbon atoms, the reaction gives rise to symmetrically substituted 1,2,3-triazoles (i.e. 1,2,3-triazoles carrying identical substituents in positions 4 and 5). If unsymmetrical substituted acetylenes are used, the resulting 1,2,3-triazoles are usually mixtures of regioisomers. Regioselectivity issues can be avoided with xcex2-ketoesters as starting materials (Bertelli et al., Eur. J. Med. Chem. 1998, 33(2), 113-122). However, xcex2-ketoesters have been used only in rare cases, and the yields have been poor. Additionally, azides are difficult to obtain, and published 1,2,3-triazole syntheses are usually not very efficient with respect to throughput and scale.
An object of the present invention is to develop a large scale, safe and efficient procedure for the syntheses of azides. Another object of the present invention is to provide an efficient one-step synthesis of triazole-carboxylic acids from azides and xcex2-keto esters.
This invention provides for a one step process for preparing 1,2,3-triazole carboxylic acids from an azide and a xcex2-ketoester. Specifically, the method of the present invention calls for the treatment of an azide and a xcex2-ketoester with a base to form a 3H-[1,2,3]triazole-4-carboxylic acid. These compounds are important precursors for antibiotics, antiallergics, antimetastasis agents, anticonvulsants and antidepressants.
The invention also provides for a method for preparing an aromatic azide intermediate from an aromatic amine. The aromatic amine is treated with a nitrate ion in the presence of an acid to form a diazonium salt. Subsequent treatment with an azide ion affords the desired aromatic azide.
The invention further provides for a method for preparing an aliphatic azide intermediate from the corresponding alkyl halide and an azide ion. The reaction proceeds via SN2 nucleophilic aliphatic substitution and the time and temperature of the reaction is dependent on the individual alkyl halide.
The invention further provides for a method for preparing a xcex2-hydroxy aliphatic azide intermediate by regioselective nucleophilic opening of an epoxide by an azide ion in the presence of ammonium chloride. For azides to be converted to the corresponding 1,2,3-triazole carboxylic acids according to the method of the present invention, the alcohol is subsequently protected.
According to Scheme 1, a preferred embodiment of the present invention relates to a method for the formation of a 3H-[1,2,3]triazole-4-carboxylic acid III by reacting an azide I with a xcex2-ketoester II in the presence of a base. 
In Scheme 1:
R1 and R2 independently are lower alkyl or cycloalkyl optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94NHC(O)-alkyl, alkenyl or alkynyl, or
R1 and R2 independently are aryl, arylalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl wherein the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94NHC(O)-alkyl, alkenyl or alkynyl; and
R3 is lower alkyl.
In a more preferred embodiment of the invention R2 is aryl or heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94NHC(O)-alkyl, alkenyl or alkynyl.
By xe2x80x9calkylxe2x80x9d, xe2x80x9clower alkylxe2x80x9d, and xe2x80x9cC1-C6 alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. These groups may be substituted with up to four groups mentioned below for substituted aryl.
By xe2x80x9calkoxyxe2x80x9d, xe2x80x9clower alkoxyxe2x80x9d, and xe2x80x9cC1-C6 alkoxyxe2x80x9d in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. These groups may be substituted with up to four groups mentioned below for substituted aryl.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine.
A xe2x80x9ccarbocyclic groupxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d is a nonaromatic cyclic ring or fused rings having from 3 to 7 ring members. Examples include cyclopropyl, cyclobutyl, and cycloheptyl. These rings may be substituted with one or more of the substituent groups mentioned below for aryl, for example alkyl, halo, amino, hydroxy, and alkoxy. Typical substituted carbocyclic groups include 2-chlorocyclopropyl, 2,3-diethoxycyclopentyl, and 2,2,4,4-tetrafluorocyclohexyl. The carbocyclic group may contain one or two heteroatoms selected from oxygen, sulfur, and nitrogen, and such ring systems may be referred to as xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d. Examples include pyranyl, tetrahydrofuranyl, and dioxanyl. These heterocyclyl groups may be substituted with up to four of the substituent groups mentioned for aryl.
By heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl. The heteroaryl group is optionally substituted with up to four groups mentioned below for substituted aryl.
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, xe2x80x94OH, xe2x80x94SH, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, trifluoromethoxy, lower acyloxy, aryl, heteroaryl, amino, mono- or dialkylamino, and nitro. A preferred aryl is phenyl.
In another more preferred embodiment, the azide I, the xcex2-ketoester II and the base are reacted together in a suitable solvent. The reaction mixture in such a solvent can be homogenous or heterogenous. Examples of suitable solvents for the present method include, but are not limited to, one or more of the following: a protic solvent such as methanol, ethanol or water; or aprotic solvents such as dimethylsulfoxide, dimethylformamide or hexamethylphosphorotriamide. In an even more preferred embodiment, the solvent is ethanol or water; and the most preferred is a combination of water and ethanol.
Examples of acceptable bases used in the present method are those with alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium, and those with organic bases including, but not limited to, amines. Preferred bases are alkali metal bases or alkaline earth metal bases. Even more preferred bases are alkaline metal carbonates, such as, for example, potassium carbonate or sodium carbonate.
In another preferred embodiment, the method of the present invention is carried out at temperatures of from between 0xc2x0 C. and 150xc2x0 C. More preferably, the reaction temperature is from between 50xc2x0 C. and 100xc2x0 C. and even more preferably the reaction temperature is from between 65xc2x0 C. and 90xc2x0 C. A most preferred temperature is around 80xc2x0 C.
Another preferred embodiment of the present invention, as depicted in Scheme 2, relates to preparing an aromatic azide intermediate Ia by reacting an aromatic amine IV with a nitrate ion to form the corresponding diazonium salt V. The diazonium salt V is then treated with an azide ion to afford the desired aromatic azide Ia. 
In Scheme 2:
Ar is aryl or heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94NHC(O)-alkyl, alkenyl or alkynyl.
In yet another preferred embodiment, Scheme 3 shows a method of preparing alkyl azide intermediates Ib by SN2 substitution of the corresponding halide VI using azide ion as the nucleophile. 
In Scheme 3:
X is a suitable leaving group, including but not limited to a halide, a mesylate or a tosylate;
R4 is lower alkyl or cycloalkyl optionally substituted with one, two or three groups independently selected from lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94C(O)O-alkyl, xe2x80x94NHC(O)-alkyl, cyano, alkenyl or alkynyl, or
R4 is aryl, arylalkyl, heteroaryl or heteroarylalkyl wherein the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94C(O)O-alkyl, xe2x80x94NHC(O)-alkyl, cyano, alkenyl or alkynyl.
Scheme 4 shows yet another preferred embodiment of the present invention, which relates to preparing xcex2-hydroxy alkyl azide intermediates Ic by regioselective nucleophilic opening of epoxide VII in the presence of ammonium chloride. 
In Scheme 4:
R4 is lower alkyl or cycloalkyl optionally substituted with one, two or three groups independently selected from lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94C(O)O-alkyl, xe2x80x94NHC(O)-alkyl, cyano, alkenyl or alkynyl, or
R4 is aryl, arylalkyl, heteroaryl or heteroarylalkyl wherein the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, xe2x80x94C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, xe2x80x94C(O)NH-alkyl, C(O)N-dialkyl, xe2x80x94C(O)O-alkyl, xe2x80x94NHC(O)-alkyl, cyano, alkenyl or alkynyl.
Even more preferably, before treatment with the xcex2-ketoester II, the xcex2-hydroxy alkyl azide intermediate Ic is protected with conventional hydroxy-protecting groups known to those skilled in the art to survive the reaction conditions of the present invention. Preferred protecting groups are those that will form ethers. Most preferably, the hydroxy group is protected as the methyl ether.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
Representative examples of methods for preparing intermediates of the invention are set forth below.